Premature ovarian failure (POF) is a term used to describe certain types of infertility in women. As many as 1% of all women in the United States are thought to be afflicted with POF, which manifests as menopausal-type symptoms, including infertility, in women under the age of 40. Many different diseases and conditions can cause POF, including underlying chromosomal defects (e.g., X-chromosome fragility), chemotherapy, or radiation treatment. Autoimmunity is a well-established mechanism of premature ovarian failure (see Yan et al., J Womens Health Gend Based Med. 9:275–87, 2000; and Kalantaridou & Nelson, J Am Med Womens Assoc. 53:18–20, 1998). In autoimmune infertility, a woman's ovaries are attacked by cells of her own immune system, leading to a condition known as autoimmune oophoritis (inflammation of the ovary). Autoimmune disease can develop in response to a single inciting antigen and then spread to involve other antigenic molecules of the same organ (Kaufman, Nature 366:69–72, 1993). Therefore, identifying the autoantigen target in an organ-specific autoimmune disease is essential to understanding its pathogenesis.
An experimental animal (mouse) model has been used to gain insight into the mechanisms of human autoimmune oophoritis. Removal of the thymus (thymectomy) in neonatal mice (about three days old) induces experimental autoimmune oophoritis in certain strains of mice (Taguchi et al., Clin Exp Immunol. 42:324–331, 1980). This experimentally induced condition leads to the production of high levels of anti-ooplasm antibodies and sterility, accompanied by follicular degeneration; the progression of the condition appears to closely parallel human autoimmune oophoritis (Kalantaridou & Nelson, J Am Med Womens Assoc. 53:18–20, 1998).
Maternal products control the developmental program until embryonic genome activation takes place. Maternal effect genes that are important in early embryonic development have been well documented in Drosophila and Xenopus (Morisato & Anderson, Annu. Rev. Genet. 29:371–399, 1995; Newport & Kirschner, Cell 30:687–696,1982), but their presence has only been inferred in mammals (Gardner, Hum. Reprod. Update 2:1–27, 1999). In mice, embryonic transcription is first detected in the late 1-cell zygote stage and is required for development beyond the 2-cell stage (Schultz, Bioessays 15:531–538, 1993; Flach et al., EMBO J. 1:681–686, 1982; Latham et al., Mol. Reprod. Dev. 35:140–150, 1993). The factors governing this transition from the maternal to the embryonic genome are unknown.
A critical transition in development occurs with the switch from dependence on proteins stored in the egg to those that result from activation of the embryonic genome. This shift which occurs at the two-cell stage in mice is dependent on maternal factors. Gene transcription and protein translation are active during murine oogenesis and RNAs and proteins accumulate within oocytes. However, germ cells becomes transcriptionally inactive late in oogenesis and much of the maternal RNA is degraded during meiotic maturation and ovulation of the egg into the oviduct. Thus, few maternal gene products persist past the two-cell embryo stage and none have been demonstrated directly to affect early development (Schultz, Bioessays 15, 531–538, 1993; Gardner, Hum. Reprod. Update 2, 3–27, 1996).